Scientific Publications

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Diagnosis of cytomegalovirus infection from clinical whole genome sequencing

Ramchandar N, Ding Y, Farnaes L, Dimmock D, Hobbs C, Kingsmore SF, Bainbridge M. 

Sci Rep. 2020 Jul 3;10(1):11020. doi: 10.1038/s41598-020-67656-5. ABSTRACT Rapid whole genome sequencing (rWGS) of peripheral blood has been used to detect microbial DNA in acute infections. Cytomegalovirus (CMV) is a herpesvirus capable of causing severe disease in neonates and immunocompromised patients. We identified CMV in patients undergoing diagnostic rWGS by matching reads that did not align to the human reference genome to a database of microbial genomes. rWGS was conducted on peripheral blood obtained from ill pediatric patients (age 1 day to 18 years). Reads not aligning to the human genome were analyzed using an in-house pipeline to identify DNA consistent with CMV infection. Of 669 patients who received rWGS from July 2016 through July 2019, we identified 28 patients (4.2%) with reads that aligned to the CMV reference genome. Six of these patients had clinical findings consistent with symptomatic CMV infection. Positive results were highly correlated (R2 > 0.99, p < 0.001) to a CMV-qPCR assay conducted on DNA isolated from whole blood samples. In acutely ill children receiving rWGS for diagnosis of genetic disease, we propose analysis of patient genetic data to identify CMV, which could impact treatment of up to 4% of children in the intensive care unit. PMID:32620939 | PMC:PMC7335102 | DOI:10.1038/s41598-020-67656-5

July 5, 2020
Gene DiscoveryrWGS


Kingsmore SF. 

Clin Chem. 2020 Jan 1;66(1):51-52. doi: 10.1093/clinchem.2019.310037.

Comment on

PMID:32609850 | DOI:10.1093/clinchem.2019.310037

July 2, 2020

Failure to thrive – an overlooked manifestation of KMT2B-related dystonia: a case presentation

Ng A, Galosi S, Salz L, Wong T, Schwager C, Amudhavalli S, Gelineau-Morel R, Chowdhury S; Rady Children’s Institute for Genomic Medicine Investigators, Friedman J.

BMC Neurol. 2020 Jun 16;20(1):246. doi: 10.1186/s12883-020-01798-x. ABSTRACT BACKGROUND: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this non-neurologic, but consequential impact of mutation in this gene. CASE PRESENTATION: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned. CONCLUSION: Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members. PMID:32546208 | PMC:PMC7296679 | DOI:10.1186/s12883-020-01798-x

June 18, 2020
Genetic Neurologic DiseaseNeurogenomicsRare Disease

Adaptive functioning in children and adolescents with Trisomy X: An exploratory analysis

Wigby K, Cordeiro L, Wilson R, Angkustsiri K, Simon TJ, Tartaglia N.

Am J Med Genet C Semin Med Genet. 2020 Jun;184(2):456-468. doi: 10.1002/ajmg.c.31803. Epub 2020 Jun 17. ABSTRACT Identifying the factors related to adaptive functioning will improve the information available to families and providers of females with Trisomy X. Cognitive and behavioral features were assessed in 50 females ages 12.2 ± 3.6 years using the Behavior Assessment System for Children Second Edition (BASC-2) and Wechsler Scales of Intelligence. Executive functioning, social skills, and autistic traits were evaluated in a subset. Adaptive functioning was assessed using the BASC-2 adaptive skills composite score (ASC). Participants were classified as average adaptive skills (ASC T-score > 40) or deficits (ASC T-score < 40). Group comparisons were conducted. Multiple linear regression examined which factors contributed to ASC score. Twenty-eight females (55.6%) had adaptive skills deficits with functional communication being the most commonly affected adaptive domain. The group with ASC in the average range had higher verbal IQ (VIQ) and lower rates of numerous behavioral concerns. Internalizing behavior composite, DSM-IV inattentive symptoms score, and VIQ were significant predictors of ASC. Prenatally diagnosed females comprised over 70% of those with average adaptive skills. In this study, internalizing behaviors, inattentive ADHD symptoms, and VIQ were associated with poorer adaptive functioning. Early interventions targeting internalizing behaviors, attention/executive functioning, and communication skills may improve adaptive skills and deserve further study. PMID:32548885 | DOI:10.1002/ajmg.c.31803

June 18, 2020

Genetic testing strategies in the newborn

Carroll J, Wigby K, Murray S.

J Perinatol. 2020 Jul;40(7):1007-1016. doi: 10.1038/s41372-020-0697-y. Epub 2020 May 29. ABSTRACT Genetic disorders presenting in the neonatal period can have a significant impact on morbidity and mortality. Early diagnosis can facilitate timely prognostic counseling to families and possibility of precision care, which could improve outcome. As availability of diagnostic testing expands, the required knowledge base of the neonatologist must also expand to include proper application and understanding of genetic testing modalities, especially where availability of clinical genetics consultation is limited. Herein, we review genetic tests utilized in the neonatal intensive care unit (NICU) providing background on the technology, clinical indications, advantages, and limitations of the tests. This review will span from classic cytogenetics to the evolving role of next generation sequencing and its impact on the management of neonatal disease. PMID:32472107 | DOI:10.1038/s41372-020-0697-y

May 31, 2020

The Medical Genome Initiative: moving whole-genome sequencing for rare disease diagnosis to the clinic

Marshall CR, Bick D, Belmont JW, Taylor SL, Ashley E, Dimmock D, Jobanputra V, Kearney HM, Kulkarni S, Rehm H; Medical Genome Initiative.

Genome Med. 2020 May 27;12(1):48. doi: 10.1186/s13073-020-00748-z. ABSTRACT Clinical whole-genome sequencing (WGS) offers clear diagnostic benefits for patients with rare disease. However, there are barriers to its widespread adoption, including a lack of standards for clinical practice. The Medical Genome Initiative consortium was formed to provide practical guidance and support the development of standards for the use of clinical WGS. PMID:32460895 | PMC:PMC7254704 | DOI:10.1186/s13073-020-00748-z

May 29, 2020
Rare Disease

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, García-Cazorla A, Honzík T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thöny B, Scholl-Bürgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhánek J, Kuseyri Hübschmann O; International Working Group on Neurotransmitter related Disorders (iNTD).

Orphanet J Rare Dis. 2020 May 26;15(1):126. doi: 10.1186/s13023-020-01379-8. ABSTRACT BACKGROUND: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies. CONCLUSION: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients. PMID:32456656 | PMC:PMC7251883 | DOI:10.1186/s13023-020-01379-8

May 28, 2020
Genetic Neurologic DiseaseNeurogenomicsRare Disease

Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability

Rasheed A, Gumus E, Zaki M, Johnson K, Manzoor H, LaForce G, Ross D, McEvoy-Venneri J, Stanley V, Lee S, Virani A, Ben-Omran T, Gleeson JG, Naz S, Schaffer A.

J Med Genet. 2021 Apr;58(4):237-246. doi: 10.1136/jmedgenet-2020-106849. Epub 2020 May 21. ABSTRACT BACKGROUND: Intellectual disability syndromes (IDSs) with or without developmental delays affect up to 3% of the world population. We sought to clinically and genetically characterise a novel IDS segregating in five unrelated consanguineous families. METHODS: Clinical analyses were performed for eight patients with intellectual disability (ID). Whole-exome sequencing for selected participants followed by Sanger sequencing for all available family members was completed. Identity-by-descent (IBD) mapping was carried out for patients in two Egyptian families harbouring an identical variant. RNA was extracted from blood cells of Turkish participants, followed by cDNA synthesis and real-time PCR for TTC5. RESULTS: Phenotype comparisons of patients revealed shared clinical features of moderate-to-severe ID, corpus callosum agenesis, mild ventriculomegaly, simplified gyral pattern, cerebral atrophy, delayed motor and verbal milestones and hypotonia, presenting with an IDS. Four novel homozygous variants in TTC5: c.629A>G;p.(Tyr210Cys), c.692C>T;p.(Ala231Val), c.787C>T;p.(Arg263Ter) and c.1883C>T;p.(Arg395Ter) were identified in the eight patients from participating families. IBD mapping revealed that c.787C>T;p.(Arg263Ter) is a founder variant in Egypt. Missense variants c.629A>G;p.(Tyr210Cys) and c.692C>T;p.(Ala231Val) disrupt highly conserved residues of TTC5 within the fifth and sixth tetratricopeptide repeat motifs which are required for p300 interaction, while the nonsense variants are predicted to decrease TTC5 expression. Functional analysis of variant c.1883C>T;p.(Arg395Ter) showed reduced TTC5 transcript levels in accordance with nonsense-mediated decay. CONCLUSION: Combining our clinical and molecular data with a recent case report, we identify the core and variable clinical features associated with TTC5 loss-of-function variants and reveal the requirement for TTC5 in human brain development and health. PMID:32439809 | DOI:10.1136/jmedgenet-2020-106849

May 23, 2020

Closing in on Mechanisms of Open Neural Tube Defects

Lee S, Gleeson JG. 

Trends Neurosci. 2020 Jul;43(7):519-532. doi: 10.1016/j.tins.2020.04.009. Epub 2020 May 15. ABSTRACT Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of the CNS. Following mandatory folic acid fortification of dietary grains, a dramatic reduction in the incidence of NTDs was observed in areas where the policy was implemented, yet the genetic drivers of NTDs in humans, and the mechanisms by which folic acid prevents disease, remain disputed. Here, we discuss current understanding of human NTD genetics, recent advances regarding potential mechanisms by which folic acid might modify risk through effects on the epigenome and transcriptome, and new approaches to study refined phenotypes for a greater appreciation of the developmental and genetic causes of NTDs. PMID:32423763 | PMC:PMC7321880 | DOI:10.1016/j.tins.2020.04.009

May 20, 2020

Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families

Issa MY, Chechlacz Z, Stanley V, George RD, McEvoy-Venneri J, Belandres D, Elbendary HM, Gaber KR, Nabil A, Abdel-Hamid MS, Zaki MS, Gleeson JG.

BMC Med Genomics. 2020 May 13;13(1):68. doi: 10.1186/s12920-020-0714-1. ABSTRACT BACKGROUND: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease. METHODS: Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease. RESULTS: Between 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011). CONCLUSIONS: Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence. PMID:32404165 | PMC:PMC7218834 | DOI:10.1186/s12920-020-0714-1

May 15, 2020

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